From Taxol(tm) to artemisinin, complex terpenes have had a profound impact on both the treatment and understanding of human disease. Despite their enormous medicinal relevance, however, most complex terpene architectures are not optimal starting points for exhaustive medicinal and chemical biological studies, and unlike many small molecule drug discovery programs, it is difficult to easily mix-and-match structural fragments. The proposed research program seeks to discover and develop simple, modular synthetic pathways to access complex, medicinally relevant terpenoid natural products. At the core of this proposal is the desire to greatly simplify terpene synthesis by using simple prenyl-derived units and chiral pool materials in concert with controlled, non-biomimetic cyclization events and polyoxygenation strategies. The targets chosen for this program represent both state of the art challenges for complex molecule synthesis as well as potential next-generation therapeutics. Complex terpenes featuring 5/8/n-fused ring systems (n = 5,6) have attractive and potent anticancer, antibacterial, and immunesuppressant properties, yet the lack of efficient synthetic methods to construct such systems has greatly hampered in-depth structure/function studies. The ophiobolin family of sesterterpenes in particular has resisted efficient chemical synthesis for several decades and new strategies are needed to efficiently construct this diverse and growing class of natural products. This work will undoubtedly lead to an enhanced SAR picture with respect to structure and function relating to their anticancer properties. Periconicin represent an emerging (and largely unexplored) class of antibacterial agents with activity against both gram positive and negative strains. Despite effort, the complex immunosuppressant variecolin has not been synthesized signifying a gap in current technologies. Highly oxygenated guaianolide terpenes represent state of the art challenges for organic synthesis and potential next generation therapeutics. Finally, terpenoid peroxides represent proven therapeutics for the treatment of malaria and are emerging as a promising class of pro-apoptotic agents for the treatment of various diseases. We have developed a remarkably simple way to construct terpene peroxide scaffolds using efficient, metal-catalyzed tandem reactions. Overall this program seeks to use advances in synthetic chemistry coupled with the inspiration of natural product architectures to construct biologically active small molecules with unprecedented efficiency and diversity. In the process of this work, students will be provided with rigorous and intellectually stimulating training in synthetic chemistry.